The Epstein Barr virus (EBV) is strongly associated with nasopharyngeal carcinoma (NPC) and plays a key role in the genesis and maintenance of the tumor phenotype in this disease. Worldwide, there are greater than 60,000 new cases of NPC reported per year, and in southern China, the incidence of NPC is 25-30 per 100,000 persons per year. The majority of patients with NPC present with advanced disease and the prognosis for these individuals is especially poor despite treatment with chemotherapy and/or radiation therapy. The EBV encoded nuclear antigen 1 (EBNA1) is an episomal replication factor that is required for maintenance of the viral genomic episome in EBV infected tissues. EBNA1 has also been shown to have tumorgenic and anti-apoptotic properties. In this application, we propose the development of small interfering RNAs (siRNAs) which specifically target the EBNA1 mRNA as a potential therapeutic approach for NPCs. Being mechanistically distinct from existing therapeutics; this approach represents a previously unexplored avenue of investigation and may have potential especially in combination with chemotherapy or radiation regimens. This work is exploratory in nature and we are therefore submitting this application through the R21 mechanism with the goal of establishing a "proof of principle" for this approach. [unreadable] [unreadable] [unreadable]